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EJRC Article Review

Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome with various etiologies that usually occurs between 24 and 48 hours after local injury (pulmonary ARDS) or generalised acute illness (extrapulmonary ARDS). It is caused by the release of pro-inflammatory cytokines, resulting in diffuse alveolar damage and varying degrees of impaired gas exchange. Approximately 10-15% of Intensive Care Units (ICU) patients meet ARDS criteria, according to the Berlin definition1, with up to 20% requiring mechanical ventilation. Even though this modality is an essential part of the syndrome’s treatment, it is in itself a cause of harm, as it can precipitate ventilator-associated lung injury (VILI) mainly due to baro-, volo-bio- and atelectrauma.2-4 Despite recent advances in critical care management, patients with moderate/severe ARDS still have high hospital mortality (41-58%) and reduced long-term quality of life.5,6

Based on the pathophysiology of VILI, two distinct lung-protective ventilation strategies have been proposed: low tidal volume/ low plateau pressure7,8 and alveolar recruitment/ Positive End-Expiratory Pressure (PEEP) titration. They both aim at the reduction of strain and stress at the alveolar level, the former by avoiding overdistention at end-inspiration and the latter by achieving and maintaining an ‘open lung’ at end-expiration. Despite adoption of lung-protective ventilation strategies in everyday ICU practice, 3 randomised control studies (RCTs)9-11 failed to demonstrate a significant reduction in mortality with recruitment manoeuvres (RM) and high levels of PEEP. A recent pilot RCT12 showed statistically significant improvement of the airway driving pressure and PaO2/fiO2 but no difference in mortality and ventilator-free days.

Attempting to answer a very important question, the Acute Respiratory Distress Syndrome (ART) investigators conducted an RCT comparing the effect of lung recruitment and titrated PEEP vs. low PEEP on mortality in patients with ARDS.13 They included 120 ICUs from 9 countries and a total of 1013 patients, 501 randomised to receive RMs and titrated PEEP, and 512 to the low PEEP strategy, as proposed by the ARDSNet9. PEEP and peak airway pressure as high as 45cmH2O and 60cmH2O respectively were used in the intervention group, who underwent a second RM (45cmH2O of PEEP) for 2 minutes. Tidal volumes were kept <6ml/kg, with plateau pressures < 30cmH2O in both groups. Their primary outcome was mortality until 28 days and secondary outcomes were length of ICU and hospital stay, ventilator-free days (day 1 to day 28), pneumothorax requiring drainage, barotrauma (within 7 days) and ICU, in-hospital and 6-month mortality. The authors reported a statistically significant higher mortality at 28-days and 6-months (55.3% vs. 49.3%, p=0.041 and 65.3% vs. 59.9%, p=0.04 respectively) in the RM/ higher PEEP group. The same group had fewer ventilator-free days (5.3 vs. 6.4, p=0.03), more cases of pneumothorax (16 vs. 6, p=0.03) and higher barotrauma rates (5.6% vs. 1.6%, p=0.001).

Discussion

The ART investigators need to be commended for their attempt to settle the burning question of how best to ventilate patients with moderate/ severe ARDS, without increasing adverse events. They conducted a large, international, multi-centre study, with robust methodology and a pre-defined study protocol. Apart from the interventions studied (RM and high, titrated PEEP), the mechanical ventilation protocol in both groups was identical, allowing for valid and generalisable results to be drawn. In fact, since the publication of their results, the PHARLAP trial (a multi-centre randomised controlled trial of an open lung strategy including Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure in patients with acute respiratory distress syndrome, NCT01667146) that used a similar RM strategy and PEEP titration, has suspended recruitment pending advice from the Data and Safety Monitoring Committee.

The surprising ART trial results can be interpreted in a number of ways; first and most importantly, high airway pressures during RMs and very high PEEP may well be detrimental to the already injured lung. The study’s experimental group was exposed to maximum PEEP of 45cmH2O and airway pressures of 60cmH2O during the recruitment period, which is probably the reason for the increased barotrauma observed in this group. The authors also chose to add 2 cmH2O of PEEP to the optimal one, which was calculated from the maximum static compliance; a decision that wasn’t explained either in the published manuscript or in the protocol. Since the difference in mean PEEP between the two groups was just 3-4cmH2O and the driving pressure difference less than 2cmH2O, with the plateau pressure and tidal volumes also being comparable, the striking difference is the much higher airway pressures during the RM in the experimental group, which might have resulted in the increased harm. Interestingly, the steering committee, in consultation with the data monitoring committee, modified the protocol mid-trial ‘after 3 cases of resuscitated cardiac arrest possibly associated with the experimental group treatment were observed’.13 After that, the maximum PEEP was reduced to 35cmH2O with a peak airway pressure of 50cmH2O for the remainder of the study.

Another possible explanation for the findings is the longer time patients in the RM/ high PEEP titration group were exposed to the higher pressures. Acknowledging that long exposure can be potentially detrimental, the investigators attempted to minimise this time by adapting their PEEP titration technique almost half way through the trial, so it lasted approximately 20min (from the initial 32min). However, that might still be enough time for barotrauma to occur, and the absence of this prolonged exposure in the control group could account for its’ decreased mortality. Furthermore, the experimental group underwent a second RM, adding to the total time its’ patients were exposed to the higher pressures.

As acknowledged by the authors, a strategy involving RM and PEEP titration is complex and associated with a number of co-interventions that need to be accounted for. In 78 cases (15.6%), the RM had to be interrupted mainly due to hypotension or hypoxia. The intervention group received more fluid (but not more vasopressors), more neuromuscular blockade and more sedation boluses (even if the median number of days receiving sedatives was not statistically different between the groups). It is difficult to evaluate the effect, if any, these co-interventions had on the mortality outcome and isolate solely the impact of the ventilatory techniques. Lastly, the ART investigators neither assessed baseline responsiveness to the RM before the intervention, nor attempted to classify the enrolled patients according to ARDS sub phenotypes. Understanding individualised data and identifying mechanism-targeted treatments, integral parts of ‘precision medicine’, aim to differentiate between patients that present with the same set of symptoms, yet possess highly specific molecular defects requiring individual treatments.14 It is possible that the intervention proposed by the ART authors could have different outcomes, depending on the specific characteristics of the recruited patients.

In conclusion, the ART trial furthers the evidence that lung RM implementing very high pressures not only fail to show the anticipated results but in fact cause harm. Based on these data, strategies that will allow lung-protective ventilation (e.g. extracorporeal devices) and enable better understanding of the heterogeneous ARDS syndrome and the individualised responses to it might provide a better focus for future research.

International consensus conferences in intensive care medicine: Ventilator-associated Lung Injury in ARDS. This official conference report was cosponsored by the AmericanThoracic Society, The European Society of Intensive Care Medicine, and The Societe de Reanimation de Langue Francaise, and was approved by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 1999;160(6):2118-24.